In addition to unraveling a new function of P0 in maintaining the integrity of paranodes/nodes of Ranvier independently of its function in maintaining myelin stability, these data identify a previously undescribed molecular mechanism that leads to pathological consequences in some disease-causing P0 mutants and suggest that other P0 mutants leading to late onset CMT may also act through the same or related pathogenesis mechanism. Here, MPZ is linked to Charcot-Marie-Tooth disease.